Blind get hope through gene therapy

For the first time, researchers have used gene therapy to increase light sensitivity and improve vision in patients who were virtually blind, a finding that offers new hope to hundreds of thousands of patients with inherited forms of vision impairment.

Although the patients had an extremely rare form of blindness called Leber’s congenital amaurosis, researchers believe the approach can ultimately be used for a much broader spectrum of disorders, including retinitis pigmentosa and macular degeneration.

The treatment, so far meant only to prove the safety of the technique, produced “real clinical benefit” and “made a real difference in patients’ lives,” said geneticist Robin R. Ali of University College London, the senior author of one of two reports presented Sunday at a Fort Lauderdale, Fla., meeting of the Assn. for Research in Vision and Ophthalmology.

The reports were also published online today by the New England Journal of Medicine.

“The fact that they had patients who could now read lines on an eye chart … and one who could run an obstacle course – this is a really great advance,” said geneticist Stephen Rose, chief research officer of the Foundation Fighting Blindness, who was not involved in the research. “This has changed the landscape of hope for patients,” he added.

Added Dr. Morton F. Goldberg, an ophthalmologist at John Hopkins University’s Wilmer Eye Institute, “In the field of retinal dystrophies, this is, I believe, the most important therapeutic discovery” in four decades. “It’s a landmark.”

The results are particularly important because gene therapy, in which a good gene is substituted for a naturally occurring defective one, has been “a snakebitten field,” with at least two subjects in other experiments dying and a handful of others developing cancer, said Dr. Albert M. Maguire of the University of Pennsylvania School of Medicine, the lead author of the second report.

A handful of children with severe combined immunodeficiency disease have been successfully treated, but critics have charged that they could have been treated equally effectively – and more safely – with conventional treatments. And three children treated for the condition in France developed leukemia because the delivery agent that was used inserted the new gene at the wrong location.

Researchers have also reported some modest benefits in gene therapy for Parkinson’s disease, but none so dramatic as the new findings with Leber’s

“We have been working for years, and it has really been rough,” Maguire said. “Here, we finally have something in a curable disease that really seems to be working.”

Leber’s congenital amaurosis affects about 3,000 people in the United States and perhaps one in every 50,000 worldwide. Children with the disorder are born with severely impaired vision that deteriorates over the course of their lives until they are totally blind in childhood or adolescence. There has been no treatment for it.

What makes Leber’s a good candidate for gene therapy is that most of the visual apparatus, including the retina, is intact – at least at birth. Typically, the defective gene that produces Leber’s is one of several in a biochemical pathway that produces chemicals necessary for the eye to generate an electrical signal for transmission to the brain.

If that gene could be replaced before the visual apparatus deteriorates from lack of use, then vision could be restored, Maguire said.

That same basic strategy could be used to treat a variety of congenital retinal disorders. “With an aging population, one of the most serious problems that hinders old people is the loss of sight,” said Dr. Katherine A. High of Children’s Hospital of Philadelphia and a co-author of one of the studies.

Retinitis pigmentosa – the broad family of disorders that includes Leber’s – affects an estimated 100,000 Americans. Macular degeneration affects 1.25 million Americans now, and the number is expected to grow to 3 million by 2020 as the population continues to age.

Those conditions are caused by other defective genes, but the treatment principle would be the same. Researchers would have to design a specific vector for each disorder bearing the proper gene.

In the latest experiment, both groups of researchers used a gene called RPE65 that is defective in many Leber’s patients. As a delivery vehicle, or vector, both groups also used an adeno-associated virus – a small virus that infects both humans and primates but is not known to cause disease. It has been shown to be safe in a variety of gene therapy experiments.

The Pennsylvania group’s vector was developed by High, while the British group used one produced by Targeted Genetics Corp. of Seattle.

The Pennsylvania group treated three patients, ages 19, 26 and 26, recruited by Dr. Alberto Auricchio of the University of Naples Federico II in Italy. Between October and January, Maguire injected a relatively small amount of the vector below the retina in each of the patient’s most severely damaged eyes.

Beginning two weeks after the injections, all three patients reported improved vision in the injected eyes, Maguire said. By measuring pupillary response to light – the only objective measure of vision that the researchers were able to employ – they found that light sensitivity had improved about three-fold. The treatment also reduced nystagmus, an uncontrollable roaming of the eye often seen in blind people.

Patients also performed better on more subjective tests. One patient’s vision on an eye chart, for example, improved from 20/640 to 20/290, about 3 1/2 lines of improvement, according to Dr. Jean Bennett, the lead author of the study. The Food and Drug Administration requires three lines of improvement to consider a treatment efficacious.

The therapy produced no inflammation in the eye or any other toxic side effects, the researchers said. One patient did develop a small hole in the retina that they believe most likely was a result of the surgery. It did not interfere with vision.

“All three subjects are asking if they can have their other eye injected,” High said. “That’s a pretty good indicator of its effectiveness.” The current protocol does not allow for that, however.

The researchers have no idea how long the improvements will persist, but dogs subjected to the treatment have remained stable for at least eight years, she said.

The British group also treated three patients with slightly smaller doses of the vector. They also found no ill effects. Their patients did not have improved visual acuity, but one of them, 18-year-old Steven Howarth, had improved light sensitivity, especially at night.

“Now, my sight when it’s getting dark or it’s badly lit is definitely better,” he said in a statement. “It’s a small change – but it makes a big difference to me.”

Howarth is “staying out later and more confident at night,” Ali said.

Both groups are now escalating the dosage of the vector and moving toward younger children whose visual apparatus has not deteriorated as much.

Ideally, High said, the treatment would be performed as soon as the disorder is diagnosed in children.

thomas.maugh@latimes.com